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Cholesterol Management and Risk Reduction
ENHANCE – After the Dust Has Settled,
Is Low-density Lipoprotein Cholesterol Lowering What It Once Was?
a report by
Evan A Stein
Director, Metabolic and Atherosclerosis Research Center, Cincinnati
The reduction of low-density lipoprotein cholesterol (LDL-C) levels is one The ENHANCE Trial – The Data
of the most well-proven interventions for reducing cardiovascular risk The ENHANCE study was designed to evaluate the effects of simvastatin
and has become a globally implemented cornerstone of treatment for alone or in combination with ezetimibe in 720 patients with
the prevention of cardiovascular disease. The lowering of serum LDL-C heterozygous familial hypercholesterolaemia (FH) and an LDL-C level of at
has been shown to not only slow the progression of atherosclerosis as least 210mg/dl following a six-week ‘wash-out’ of all lipid-lowering
assessed by anatomical surrogates such as carotid ultrasound and drugs.
24
A number of previous epidemiological studies in the general
coronary intravascular ultrasound, but more importantly also to decrease population showed a strong correlation between carotid intima-media
the incidence of cardiovascular events and mortality.
1,2
The most thickness (cIMT) and cardiovascular events, as well as correlations
effective and widely used LDL-C-lowering agents are the 3-hydroxyl-3- between cIMT and a number of well-established risk factors for
methylglutaryl coenzyme A reductase (HMG-CoAse) inhibitors, better cardiovascular disease such as age, sex, LDL-C, blood pressure and
known as statins, which function by inhibition of hepatic cholesterol diabetes.
25
The design of ENHANCE was based on that of the
synthesis and upregulation of LDL-C receptors.
1
More aggressive LDL-C Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP), a
reduction by either higher doses of the same statin or use of more smaller trial carried out in a similar FH population in Holland in the mid-
efficacious statins has been demonstrated in placebo-controlled, 1990s that compared the effects of simvastatin 40mg versus atorvastatin
prospective, randomised trials to achieve further reductions in the rates 80mg on atherosclerotic progression as measured by cIMT.
26,27
As in
of cardiovascular disease.
2–7
Small but significantly greater reductions in ASAP, the primary outcome in ENHANCE was the change in mean cIMT
LDL-C can also be achieved at the highest approved doses of the three from baseline as measured by ultrasonography, defined as a composite
most used statins (simvastatin, atorvastin and rosuvastatin), with 80mg measure of the mean of the thicknesses in the far walls of the right and
of simvastatin being equivalent to 40mg of atorvastatin and 80mg of left common carotid arteries, carotid bulbs and internal carotid arteries.
atorvastatin being equivalent to 20mg of rosuvastatin.
8
However, within Secondary outcomes included the change in the mean maximal cIMT
the dose range of any statin, the highest approved dose offers only a (the thickest of the six baseline measurements) from baseline, changes
limited additional LDL-C reduction of approximately 6% from the in the average mean IMT of the six carotid sites and the common femoral
second highest dose, but at the expense of an increased incidence of a arteries from baseline and the proportion of patients who developed new
number of adverse effects.
9–12
Furthermore, there are many high-risk carotid-artery plaques exceeding 1.3mm.
patients in whom adequate LDL-C levels cannot be achieved with statins
alone, not even with rosuvastatin 40mg.
13
Such patients are prescribed After 24 months of daily treatment there was no significant difference
a second agent that complements the action of statins, such as niacin, (p=0.29) in the primary outcome measure: the change in mean cIMT
bile acid sequestrants (BAS) or cholesterol absorption transport inhibitors from baseline was 0.0058±0.0037 in the simvastatin-only group and
(CATi), in order to achieve their therapeutic goals. Ezetimibe, a CATi, 0.0111±0.0038 in the group receiving the ezetimibe/simvastatin
binds to the Niemann-Pick C1-like 1 (NCP1L1) protein, selectively combination.
23
Secondary outcomes were also similar between groups:
inhibiting the absorption of biliary and dietary cholesterol at the mean cIMT regression was 44.4% in the simvastatin group and 45.3% in
intestinal wall.
14–16
Studies have shown that ezetimibe produces a the combination group (p=0.92); changes in the mean maximum cIMT
reduction in LDL-C levels of approximately 18%, irrespective of whether were non-significant, with an increase of 0.0103±0.0049mm in the
it is given as monotherapy or as an adjunct to existing stable doses of simvastatin group and 0.0175±0.0049mm in the combination group
any other statin.
17,18
It also produces a small but significant increase in (p=0.27); and new plaque formation was seen in 2.8% of the simvastatin
high-density lipoprotein cholesterol (HDL-C) and reductions in group and 4.7% of the combination group (p=0.20). There were no
triglycerides and apolipoprotein B.
19–21
Studies have also shown an
approximate doubling in the reduction of the inflammatory marker high-
Evan A Stein is Director of the Metabolic and Atherosclerosis
sensitivity C-reactive protein (hsCRP) when ezetimibe is co-administered
Research Center in Cincinnati, and is one of the ENHANCE
with a statin compared with statins alone.
22
investigators. In 2006 he was appointed to the US Food and
Drug Administration (FDA) Clinical Chemistry and Clinical
Toxicology Advisory Panel, a position he will hold until
The neutral results from the recent Ezetimibe and Simvastatin in Familial
2010. Dr Stein has authored or co-authored more than 210
Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE)
publications in the area of lipid metabolism and laboratory
medicine, is on the Editorial Board of the Journal of Clinical
trial
23
have led to some questioning of the cardiovascular benefits of
Lipidology and is past Editor of the Statin section of Current
ezetimibe and the LDL-C hypothesis in general. This article will review the Atherosclerosis Reports.
issues raised by the ENHANCE trial and the clinical implications for future
E: esteinmrl@aol.com
studies and LDL-C-lowering therapy.
© TOUCH BRIEFINGS 2008 21
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